Original Article
Ghrelin, Resistin and Leptin Levels in
Patients with Metabolic Syndrome
Fatih Koç1, Mehmet Tokaç2, Volkan Kocabaş3, Coşkun Kaya4, Sadık Büyükbaş3, Sami Erdem3, Turgut
Karabağ2, Kenan Demir2, Yusuf Alihanoğlu2, Ahmet Kaya4
Gaziosmanpasa University School of Medicine, Department of Cardiology, Tokat
1
Selcuk University School of Medicine,
Departments of Cardiology2, Biochemistry3
and Internal Medicine4 Konya, Turkey
2-4
Eur J Gen Med 2011;8(2):92-7
Received: 27.08.2010
Accepted: 12.11.2010
ABSTRACT
Aim: This study was designed to compare the fasting ghrelin, leptin
and resistin levels between metabolic syndrome (MS) patients with
healthy controls.
Method: This trial was performed on 21 patients with MS (7 men;
mean age, 44±4 years) and 17 healthy controls (8 men; mean age, 43±3
years). Diagnosis of MS was defined based on National Cholesterol
Education Program (NCEP) Adult Treatment Panel (ATP) III criteria.
Patients meeting at least 3 of the MS criteria, with a body mass index (BMI) ≥30 kg/m² were included in the MS group. Among healthy
volunteers, those with a BMI<30 kg/m² were selected as the control
group. Plasma ghrelin, serum leptin and resistin concentrations were
measured by ELISA method.
Result: Ghrelin levels were similar between MS and control groups.
There was a negative correlation detected between ghrelin levels
with BMI and leptin levels (r=-.54, P=.01 and r=-.56, P=.009, respectively). Resistin levels were found similar between MS with control
groups. Leptin levels were significantly higher at the MS group than
control group (35±17 ng/ml vs. 14±8 ng/ml, P=.001). Leptin levels had
a positive correlation with BMI (r=.56; P=.008).
Conclusion: We have demonstrated that leptin levels in MS group
were higher than control group. However, ghrelin and resistin levels
were similar to control group. In addition, we have showed leptin
levels has a positive correlation with BMI and a negative correlation
with ghrelin levels.
Key words: Metabolic syndrome, obesity, ghrelin, resistin, leptin.
Correspondence: Fatih Koç, MD
Gaziosmanpasa University School of Medicine Department of Cardiology, 60100,
Tokat/Turkey,
Tel: 905554641141, Fax: 903562133179
E-mail: [email protected]
European Journal of General Medicine
Ghrelin, resistin and leptin in metabolic syndrome
Metabolik Sendromlu Hastalarda Grelin, Rezistin ve Leptin Düzeyleri
Amaç: Bu çalışmada metabolik sendromlu (MS) hastalar ile sağlıklı kontroller arasında açlık ghrelin, leptin ve resistin düzeylerinin karşılaştırılması amaçlanmıştır.
Metod: Çalışmaya 21 MS hastası (7 erkek; ortalama yaş, 44±4) ve 17 sağlıklı kontrol (8 erkek; ortalama yaş 43±3) alınmıştır. MS
tanısı Ulusal Kolesterol Eğitim Programı (NCEP) Erişkin Tedavi Paneli (ATP) III kriterlerine göre tanımlandı. MS karşılama kriterlerinden en az 3’üne sahip olan ve beden kitle indeksi (BKI) ≥30 kg/m² olan hastalar MS grubuna seçildi. Sağlıklı gönüllüler arasında
BKI <30 kg/m² olanlar kontrol grubu olarak seçildi. Plazma ghrelin, leptin ve resistin düzeyleri ELISA yöntemi ile ölçüldü.
Bulgular:Ghrelin düzeyleri MS ve kontrol grupları arasında benzerdi. Ghrelin ve Leptin seviyeleri ile BKİ arasında negatif bir ilişki
tespit edildi (r=-.54, P=.01 ve r=-.56, p= 0.009, sırasıyla). Resistin düzeyleri kontrol grubu ile MS arasında benzer bulundu. Leptin
düzeyleri kontrol grubuna göre MS grubunda (35±17 ng/ml ve 14±8 ng/ml, p= 0.001) anlamlı derecede daha yüksek bulundu. Leptin
düzeyleri ile BKİ arasında pozitif korelasyon vardı (r =0.56; p= 0.008). Biz MS grubunda leptin düzeylerinin kontrol grubuna göre
daha yüksek olduğunu gösterdik. Ancak, ghrelin ve resistin düzeyleri kontrol grubuna benzerdi.
Sonuç: Sonuç olarak biz leptin düzeyleri ile BKİ arasında pozitif bir ilişki olduğunu ve ghrelin seviyeleri ile negatif ilişkili olduğunu
gösterdik.
Anahtar kelimeler: Metabolik sendrom, obezite, ghrelin, resistin, leptin
INTRODUCTION
Obesity is a community health problem affecting over
one billion adult persons worldwide (1). Obesity is closely
related to insulin resistance, hiperinsulinemia, glucose
intolerance, dislipidemia, hypertension (HT), premature
atherosclerosis and increased risk for coronary artery disease (CAD). The situation that these abnormalities being together are called insulin resistance syndrome or
metabolic syndrome (MS) (2). Although there are many
considerations to explain the basis of these metabolic abnormalities, the main mechanism of disease has not been
determined yet (3).
It has recently been thought that some new regulatory
peptides might be playing a key role on the pathogenesis
of MS (4). One of these peptides is ghrelin hormone having a number of metabolic and cardiovascular (CV) effects (5). Ghrelin being an endogenous ligand for the secretory receptor of growth hormone is a peptide hormone
secreted by stomach and small bowel (6). Low ghrelin
level in blood is related to the components of MS such as
obesity, insulin resistance and blood pressure (7). Ghrelin
has a direct effect on energy consumption metabolism
and increases food intake beside other metabolic properties (8,9). The previous studies have showed that intact ghrelin signals are quite important in occurrence of
diet induced obesity. The ghrelin level in obese persons
is higher than that of lean individuals and also a negative
relationship has been detected between ghrelin level and
93
body mass index (BMI) (8). Leptin is also a peptide hormone like ghrelin and there is a negative interaction on
appetite between leptin and ghrelin (10). Leptin is mainly
secreted by adipose tissue and has anorexigenic functions
(11). A positive correlation between BMI and leptin has
been demonstrated in the previous studies (12). Recently
published studies have showed that leptin secretion has a
significant effect on central regulation as much as ghrelin
(13). Ghrelin is down regulated by insulin and leptin in
human obesity. Therefore, leptin and ghrelin have a key
role on development of MS and diabetes mellitus (DM)
while genetic, environmental and hormonal factors are
affecting the process (10). Resistin is a new adipocytokin and mainly secreted by adipose tissue and peripheral
mononuclear blood cells in human (14-16). It has been
claimed that this molecule is related to metabolic signals, inflammation, and atherosclerosis. Its expression
is up regulated by proinflammatory cytokines. There are
some studies referring to the role of this molecule in obesity, insulin resistance and increase in blood glucose level
(14).
The aim of this study is to investigate the levels of ghrelin, resistin and leptin in patients with MS, and to show
the association with the parameters of MS.
Eur J Gen Med 2011;8(2):92-7
Koç et al.
Table 1. Baseline Characteristics and Study Parameters in Metabolic Syndrome and Control Groups
Metabolic Syndrome
n:21
Control
n:17
p value
Age (years)
44±4.0
Gender (male/female)
7/14
Waist circumference (cm)
113±12
Body mass index (kg/m²)
36±5.0
Blood pressures (mmHg)
Systolic 142±16
Diastolic 95±11
Fasting blood glucose (mg/dL)
102±13
Total Cholesterol (mg/dL)
186±36
HDL Cholesterol (mg/dL)
43±8.0
LDL Cholesterol (mg/dL)
114±29
Triglyceride (mg/dL)
161±82
Study Parameters
Ghrelin (fmol/mL)
127±46
Resistin (ng/mL)
0.99±0.41
Leptin (ng/mL)
35±17
43±3.0
8/9
85±9.0
25±2.0
0.12
0.39
0.001
0.001
118±6.0
83±12
95±10
183±24
47±7.0
117±25
86±38
0.001
0.003
0.08
0.77
0.07
0.74
0.001
158±78
1.16±0.48
14±8.0
0.16
0.26
0.001
MATERIALS AND METHODS
Ghrelin, resistin and leptin measurement
Study Population
All obtained serum and plasma samples after overnight
fasting (12 hours) were collected from antecubital vein.
For Ghrelin measurements blood was directly drawn in
to a centrifuge tube that contains 500 U of Aprotinin and
1.25mg of EDTA-2Na per 1 mL of blood. All tubes were
immediately centrifuged at 1500 x g for 15 minutes at
+4oC. Then plasma samples were separated. For Resistin
and Leptin measurements blood samples were obtained
in to a serum tube that contains no anti-coagulant. All
tubes were waited to let blood clot at room temperature for 30 minutes. Clotted blood centrifuged at 3000
x g for 15 minutes at +4oC. Then serum samples were
separated. All serum and plasma specimens were stored
at a – 80oC for approximately 2 months until all samples
were collected and analyzed. Plasma Ghrelin and serum
Leptin and Resistin concentrations were measured by
ELISA method (Linco Research, Missouri, USA) according
to the instructions of the manufacturer.
A total of 38 individuals were enrolled in the study after
getting consent, including 21 patients with MS (group I,
7 men; mean age, 44±4 years) and 17 healthy controls
(group II, 8 men; mean age, 43±3 years). Approval was
obtained from the local ethical committee.
Diagnosis of MS was defined based on National
Cholesterol Education Program (NCEP) Adult Treatment
Panel (ATP) III criteria (17). Patients meeting at least 3
of the MS criteria, with a BMI ≥30 kg/m² were included
in the MS group (group I). Body mass index was calculated, dividing the patient weight by the square of height
in square meters. Among healthy volunteers, those with
a BMI<30 kg/m² were included as the control group
(group II). Waist circumference was measured with a
soft tape on standing individuals midway between the
lost rib and the iliac crest. The blood pressure was measured on both arms by the physician after 15 minutes of
resting while the patient was in sitting position and the
mean value was obtained. Following 12 hours of fasting, venous blood sample was obtained from all patients
and fasting blood glucose (FBG) and lipid panel was
measured. Exclusion criteria included coronary cardiac
disease history, cardiomyopathy, chronic lung disease,
DM, antihypertensive drug use, creatinine >2.0 mg/dl,
malignancy.
Eur J Gen Med 2011;8(2):92-7
Statistical analysis
Statistical analysis was performed using designated software (SPSS 13, SPSS Inc., Chicago, Illinois). Continuous
variables are expressed as mean±SD. Continuous variables between groups were compared ‘Student’s t test’
or ‘Mann-Whitney U’ test as appropriate. Categorical
variables are presented as absolute values and comparisons were tested using chi-square test. Pearson’s correlation test was used to demonstrate the correlations
94
Ghrelin, resistin and leptin in metabolic syndrome
Figure 1. Correlations were showed among ghrelin, leptin and BMI.
between the data exhibiting parametric distribution. A
p values <0.05 are considered statistically significant.
RESULTS
Clinical Features
The basic characteristics of groups are presented in
Table. There was no difference between the MS and
control groups with respect to age and gender. The waist
circumference and BMI were significantly higher at the
MS group compared to the control group. Systolic and
diastolic blood pressure, triglyceride (TG) levels were
different between the MS and control group.
Ghrelin, resistin and leptin levels
Ghrelin, resistin and leptin levels are presented in
Table. Ghrelin levels were similar between MS and control groups. There was a negative correlation between
ghrelin levels and BMI in MS group (r= -0.54, p= 0.01).
Resistin was also found similar between MS and control
groups. Leptin levels were significantly higher in MS
group compare to control group (p= 0.001). There was
a positive correlation between leptin levels and BMI in
MS group (r= 0.56, p= 0.008). There was a negative correlation between ghrelin and leptin levels in MS group
(r= -0.56, p= 0.009) (Figure 1). Ghrelin, leptin and resistin were not considerably associated with the other MS
parameters such as FBG, HDL cholesterol, TG and blood
pressure.
DISCUSSION
In this study, leptin found considerably higher in patients
95
with MS than control group. Also a positive correlation
between leptin levels and BMI, a negative correlation
between leptin and ghrelin levels has been demonstrated (6,10,12). On the other hand, there was no difference for resistin between the MS and control groups.
Even a small but chronically problem to come into existence between energy intake and consumption may be
resulted in obesity. Obesity, DM, CAD and hypertension
are closely related to increased mortality (18). High
level of leptin is an important marker of MS in obese
patients. In some studies, it has been shown that obesity, MS, and cardiovascular risk factors are closely associated with increase in leptine level (19). Leptin is a
major hormone having properties such as suppression of
food intake and making energy consumption increased,
however it can also enhance peripheral insulin sensitivity and pancreatic β-cell function independent of these
features (1). Leptin level in obese and overweight persons have a positive correlation with BMI, however it
has a negative correlation with ghrelin (20). It has been
noted in the previous studies that high leptin and low
ghrelin level are associated with MS, DM and premature atherosclerosis (10). In this study, significant positive correlation between leptin and BMI and a negative
correlation between leptin and ghrelin has been determined concordant with the literature (12,20).
Ghrelin is a somatotropic and orexigenic hormone;
however it has quite important regulatory functions on
energy metabolism (19). Ghrelin increases food intake
by performing direct effect on it and decreases energy consumption. However, direct infusion of ghrelin
increases blood glucose level, decreases glucose tolerance and restricts releasing of insulin (8). In some
Eur J Gen Med 2011;8(2):92-7
Koç et al.
studies, plasma ghrelin level in insulin-resistant obese
individuals has been found lower than that of insulin
sensitive ones and it has been shown that MS and DM are
associated with ghrelin (10,16). Ghrelin level in many
obese persons tends to be lower than that of underweight persons (16,21). It has been asserted that this
condition might be an adaptive response to make weight
decreased in obese persons (22). In this study, ghrelin
was similar in patients with MS and healthy cotrols. In
literature, a negative correlation between ghrelin level and BMI has been determined in both of obese and
normal weight persons (8,20). In this study as well, we
have demonstrated a considerable negative correlation
between ghrelin and BMI in patients with MS. In previous
studies, a negative relation between ghrelin concentration and waist circumference has been detected (2224). However, in our study, we were unable to detect a
considerable negative correlation between ghrelin concentration and waist circumference in MS group.
Resistin is a peptide hormone secreted by adipose tissue and its effects on glucose and insulin metabolism
are controversial (1,16). It has been stated that resistin could cause MS and obesity through increasing insulin resistance and metabolic enzyme transcription
(14). Although some investigators claimed that resistin
was associated with obesity and DM, this result could
not been confirmed by the other studies (1). Recently
published studies have claimed that inflammatory molecules in endothelial cells up regulate resistin secretion
and that resistin may be an important marker for atherosclerosis in human (14,25). The relation between resistin concentration and increased coronary arterial calcification has been shown in a study performed in MS patients (26). Resistin concentration was found increased
in a study performed in patients with acute coronary
syndrome (14). In this study we have found that resistin
levels were similar between MS and control groups. And
also, any considerable relevant between parameters of
MS and resistin level could not be demonstrated.
We have found that leptin levels in MS group were higher but ghrelin and resistin levels were similar to control
group. Leptin had a positive correlation with BMI and a
negative correlatin with ghrelin. Also these hormones
were not considerably associated with the other MS parameters such as waist circumference, FBG, HDL cholesterol, TG and blood pressure. This study and further
researches can be guidance for effective treatment of
MS and obesity in the future.
Eur J Gen Med 2011;8(2):92-7
Acknowledgments
The author thanks Dr. Mohamed Mohy Amin and Dr. Hassan shawky for their skilful
assistance in selection of participants and during clamp procedures of this study.
Author is grateful for the cooperation and support of all patients who participated
in this study.
REFERENCES
1.
Rabe K, Lehrke M, Parhofer KG, et al. Adipokines and insulin resistance. Mol Med 2008;14:741-51.
2.
Hamdy O, Ledbury S, Mullooly C, et al. Lifestyle modification improves endothelial function in obese subjects
with the insulin resistance syndrome. Diabetes Care
2003;26:2119-25.
3.
Ukkola O and Bouchard C. Clustering of metabolic abnormalities in obese individuals: the role of genetic factors.
Ann Med 2001;33:79-90.
4.
Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y
Acad Sci 1999;892:146-54.
5.
Kojima M and Kangawa K. Ghrelin: structure and function. Physiol Rev 2005;85:495-22.
6.
Luis DA, Aller R, Izaola O, et al. Influence of insulin
resistance and adipocytokines on elevated serum alanine aminotransferase in obese patients. Arch Med Res
2008;39:110-14.
7.
Ukkola O, Pöykkö SM, Antero Kesäniemi Y. Low plasma
ghrelin concentration is an indicator of the metabolic
syndrome. Ann Med 2006;38:274-79.
8.
Nogueiras R, Tschöp MH, Zigman JM. Central nervous
system regulation of energy metabolism: ghrelin versus
leptin. Ann N Y Acad Sci 2008;1126:14-9.
9.
Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances
appetite and increases food intake in humans. J Clin
Endocrinol Metab 2001;86:5992-95.
10. Ukkola O, Poykko S, Paivansalo M, et al. Interactions
between ghrelin, leptin and IGF-I affect metabolic syndrome and early atherosclerosis. Ann Med 2008;29:1-9.
11. Savino F, Liguori SA. Update on breast milk hormones:
leptin, ghrelin and adiponectin. Clin Nutr 2008;27:42-7.
12. Schur EA, Cummings DE, Callahan HS, et al. Association of
cognitive restraint with ghrelin, leptin, and insulin levels
in subjects who are not weight-reduced. Physiol Behav
2008;93:706-12.
13. Shintani M, Ogawa Y, Ebihara K, et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the
activation of hypothalamic neuropeptide Y/Y1 receptor
pathway. Diabetes 2001;50:227-32.
14. Chu S, Ding W, Li K, et al. Plasma resistin associated with
myocardium injury in patients with acute coronary syndrome. Circ J 2008;72:1249-53.
96
Ghrelin, resistin and leptin in metabolic syndrome
15. Savage DB, Sewter CP, Klenk ES, et al. Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes
2001;50:2199-202.
16. Bideci A, Camurdan MO, Yeşilkaya E, et al. Serum ghrelin,
leptin and resistin levels in adolescent girls with polycystic ovary syndrome. J Obstet Gynaecol Res 2008;34:57884.
17. Executive Summary of The Third Report of The National
Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation, And Treatment of High Blood
Cholesterol In Adults (Adult Treatment Panel III). JAMA
2001;285:2486-97.
18. Yingzhong Y, Droma Y, Rili G, et al. Regulation of body
weight by leptin, with special reference to hypoxia-induced regulation. Intern Med 2006;45:941-46.
19. Yoshinaga M, Sameshima K, Tanaka Y. Adipokines and the
prediction of the accumulation of cardiovascular risk factors or the presence of metabolic syndrome in elementary school children. Circ J 2008;72:1874-78.
20. Daghestani MH, Ozand PT, Al-Himadi AR, et al. Hormonal
levels of leptin, insulin, ghrelin, and neuropeptide Y in
lean, overweight, and obese Saudi females. Saudi Medical
Journal 2007;28:1191-97.
97
21. Tschop M, Weyer C, Tatarannı PA, et al. Circulating
ghrelin levels are decreased in human obesity. Diabetes
2001;50:707-09.
22. Park HS, Lee KU, Kim YS, et al. Relationships between
fasting plasma ghrelin levels and metabolic parameters
in children and adolescents. Metabolism 2005;54:925-29.
23. Monti V, Carlson JJ, Hunt SC, et al. Relationship of ghrelin and leptin hormones with body mass index and waist
circumference in a random sample of adults. J Am Diet
Assoc 2006;106:822-28.
24. Ikezaki A, Hosoda H, Ito K et al. Fasting plasma ghrelin
levels are negatively correlated with insulin resistance
and PAI-1, but not with leptin, in obese children and adolescents. Diabetes 2002;51:3408-11.
25. Verma S, Li SH, Wang CH et al. Resistin promotes endothelial cell activation: Further evidence of adipokine-endothelial interaction. Circulation 2003;108:736-40.
26. Reilly MP, Lehrke M, Wolfe ML, et al. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation
2005;111:932-39.
Eur J Gen Med 2011;8(2):92-7